24. The Clinical Development of Lumateperone (ITI-007) for the Treatment of Schizophrenia

Abstract

Background: Schizophrenia affects about 1% of the population and exerts a great burden on patients and caregivers. Newer treatments are needed to provide broad symptom control and improved tolerability. Lumateperone is an investigational agent in late-stage development for schizophrenia, bipolar depression and agitation associated with dementia. Through synergistic actions via serotonergic, dopaminergic and glutamatergic systems, lumateperone represents a novel therapeutic approach.Methods: The late-stage schizophrenia program comprised three well-controlled trials in patients during an acute exacerbation. ITI-007-005 included 335 patients randomized to receive either lumateperone (60 mg or 120 mg), risperidone (positive control) or placebo for 4 weeks.ITI-007-301 included 450 patients randomized to receive either lumateperone (60 mg or 40 mg) or placebo for 4 weeks. ITI-007-302 included 696 patients randomized to receive either lumateperone (60 mg or 20 mg), risperidone (positive control) or placebo for 6 weeks. The primary efficacy end point in all studies was PANSS total score change from baseline versus placebo.Results: In studies ITI-007-005 and ITI-007-301, lumateperone 60 mg met the primary end point and demonstrated efficacy with statistically significant superiority over placebo at Day 28. Lumateperone 60 mg, which requires no dose titration, also showed early efficacy (week 1) on both the PANSS total score and the PANSS Positive Symptom subscale score in ITI-007-301, and maintained efficacy throughout the study. In ITI-007-301, lumateperone 60 mg also met the key secondary endpoint of statistically significant improvement on the CGI-S. In this study, lumateperone 40 mg separated significantly from placebo on the PANSS positive subscale and the CGI-S, but not on the primary endpoint. Pro-social benefits were also observed with lumateperone in both studies.In ITI-007-302, neither dose of lumateperone separated from placebo on the primary endpoint in the pre-defined patient population. Risperidone did separate from placebo. While the same magnitude and trajectory of improvement with lumateperone 60 mg was observed in all 3 studies (005, 301 and 302), an unusually high placebo response was observed in this last study. Post-hoc analyses revealed improved treatment effects for lumateperone when placebo response was controlled for.Across all studies, lumateperone was well tolerated and exhibited a safety profile similar to placebo. In 2 studies that included risperidone as an active control, lumateperone demonstrated statistically significant advantages over risperidone on key safety and tolerability parameters.Conclusion: Lumateperone represents a new approach to the treatment of schizophrenia with unique pharmacology and a differentiating clinical profile.